This PPG examines genetic regulation of brain formation and function from the perspective of cortical[unreadable] interneuron development. Increasing evidence suggests that selective developmental interneuron deficits[unreadable] are intimately linked with,failure of neural progenitor proliferation and specification. Lost function of the cell[unreadable] cycle gene cyclin D2 results in reduced brain volumes and selective loss of interneurons, e.g. cerebellar[unreadable] stellate and granule neurons, while sparing basket and Golgi interneurons as well as projection (Purkinje)[unreadable] neurons (Ross, Projl). Studies of neurogenic divisions in the cerebral cortical VZ suggest that GABAergic[unreadable] interneurons influence proliferation and differentiation of cortical neural cells (Kriegstein, ProjS). Evidence in[unreadable] rodent models suggests that most cortical interneurons originate from the medial ganglionic eminence[unreadable] (MGE) (Anderson, Proj2); thus investigations of interneuron development must involve MGE. The goal of[unreadable] the Program is to tease out the relative contributions of inteneuronal populations to brain formation,[unreadable] structure and function, examining the role of proliferation and interneuron specification to brain[unreadable] development.[unreadable] Project 1 will examine the consequences of reduced cell proliferation in brains of mice lacking cyclin D2,[unreadable] associated with small telencephalon and selective interneuron deficits. Conditional knockouts of cyclin D2[unreadable] that further restrict the neural cell populations affected will be used to examine the dynamic role of specific[unreadable] neural subpopulations in brain formation.[unreadable] Project 2 will pursue the roles of Shh signaling to 1) specify cortical interneurons that originate in the[unreadable] MGE, and 2) (collaborating with Project 3) to regulate proliferation within the cortex. Several Cre-loxP[unreadable] conditional nulls will be examined with distinct patterns inactivating Shh or its receptor in the embryonic[unreadable] forebrain. These mice and in vitro studies will be used to explore the multiple roles of Shh on cortical[unreadable] neurogenesis.[unreadable] Project 3 will examine the dynamic behavior of neurogenic divisions in the VZ and SVZ of the MGE[unreadable] compared to cortex to determine how intrinsic and epigenetic factors modulate neurogenesis, and how[unreadable] regional alterations in the pattern of division might contribute to developmental interneuron deficits.[unreadable] Project 4 will examine the neurophysiology and behavioral consequences of the selective alterations of[unreadable] interneuronal subpopulations in animal models produced by Projects 1 and 2.[unreadable] The Projects are supported by administrative, statistical, histological and quantitative neuroanatomical[unreadable] services provided in Cores A and B.[unreadable] These genetic mouse models with highly selective interneuron deficits enable the Program to examine the[unreadable] contributions of neuron subsets to brain structure, complex behaviors and cognitive function. The proposed[unreadable] studies are relevant to epilepsy, schizophrenia, affective disorders and cognitive disorders including autism.[unreadable]